Persistent high levels of virus are the primary driver of immunodeficiency in HIV infection, predicting progression to AIDS (Mellors et al., 1995). A key feature of the immune system that also affects the tempo of disease progression is immune activation; in fact, it is the strongest known predictor of CD4+ loss and time to AIDS (Liu et al., 1997; Giorgi et al., 1999; Deeks et al., 2004). Non-specific immune activation is a hallmark of chronic HIV infection; its importance is highlighted by lack of disease progression in natural hosts of SIV and rare HIV-infected humans that have high viral loads but little immune activation (Silvestri et al., 2003; Choudhary et al., 2007), illustrating that de-linking viral replication and immune activation can prevent disease progression. Two major manifestations of immune activation are expression of activation markers on T cells, and increased T cell turnover (Hellerstein et al., 1999). CCR5-expressing CD4+ effector memory (TEM) cells at tissue effector sites are the main target of HIV, and are short-lived due to both viral cytolysis and activation-induced apoptosis (Finkel et al., 1995). These cells are easily replaced by naove and central memory (TCM) precursors. Important insights into the dynamics of the TCM-TEM balance have been gained from studies in SIV-infected macaques, which suggest that chronic immune activation drives differentiation of CD4+ TCM to replace CD4+ TEM depleted in tissues, and this gradual loss eventually exhausts TCM resources and leads to disease (Okoye et al., 2007). Importantly, preserved CD4+ TCM were a correlate of lower viral loads and longer survival in macaque models of infection and vaccination (Letvin et al., 2006; Karlsson et al., 2007; Sun et al., 2007; Mason et al., 2008). The overall aim of this project is to investigate how CD4+ memory cell subsets, particularly CD4+ TCM, impact on disease progression in HIV infection, and their relationship with immune activation. We hypothesize that CD4+ central memory cell depletion driven by immune activation influences the tempo of disease progression in HIV infection. We further hypothesize that immune activation pre-infection may influence HIV susceptibility and the number of CD4+ central memory cells pre-infection influences disease progression. We have a unique cohort of untreated HIV-1 subtype C infected individuals that have been monitored pre-infection, during acute infection and are being followed longitudinally over the course of chronic infection. We propose to monitor (1) levels of immune activation and (2) CD4+ memory subset dynamics in this cohort to elucidate mechanisms of disease progression in HIV infection. Current therapy for HIV is directed at inhibiting the virus. A better understanding of the damage caused to the affected organ (the immune system) and how it influences disease progression may lead to new immune therapeutic targets. Limiting immune activation and preserving CD4+ central memory cells may represent viable non-viral targets for intervention. PUBLIC HEALTH RELEVANCE: South Africa has one of the largest HIV epidemics in the world, with over 5 million South Africans infected, representing approximately 12 % of the population. A better understanding of the immunological and viral mechanisms that influence the time till development of AIDS may lead to the development of new therapies targeting the damaged immune system, leading to longer AIDS-free survival times prior to initiation of antiretroviral therapy.